JPS61215342A - Production of optically active 4-hydroxy-2-substituted-2-cyclopentenone - Google Patents

Abstract

PURPOSE:To obtain the titled substance by reacting a lactone with a 4- hydroxy-2-substituted-2-cyclopentenone at a specific molar ratio in the presence of a specific catalyst and hydrolyzing the reaction product separated easily from a mixture containing one of the optical isomer in excess. CONSTITUTION:The objective compound of formula III is produced by (1) reacting (A) the 4-hydroxy-2-substituted-2-cyclopentenone of formula I (R is allyl or propargyl) with (B) a lactone such as (1R, 5S)-6,6-dimethyl-4-hydroxy-3- oxabicyclo[3,1,0]hexan-2-one at a molar ratio of 1.5-2:1 in the presence of p-toluenesulfonic acid or benzenesulfonic acid as a catalyst under azeotropic dehydration in an azeotropic solvent to obtain a reaction mixture containing the condensation products of formula II wherein either one of the optically active isomer is present in excess to its antipode, (2) separating an optically active cyclopentenone ether compound therefrom and (3) hydrolyzing the ether.

Description

Detailed Description of the Invention The present invention provides an optically active 4-hydroxy-2-substituted-2-cyclobentenone represented by the general formula (I) υ (wherein R represents an allyl group or a propargyl group). Concerning the manufacturing method.

The optically active 4-hydroxy-2-substituted-2-cyclobentenone represented by the general formula (X) is a very useful compound in medicine and agrochemicals, for example, as an important intermediate of prostaglandin or It is used as a raw material for a new type of prostaglandin derivative.

Such optically active 4-hydroxy-2-substituted-2-cyclobentenones, such as 4-hydroxy-2-allyl-2
- As a method for obtaining cyclobentenone, JP-A-58-
A method described in Japanese Patent No. 41886 is known.

This method involves reacting 4-hydroxy-2-allyl-2-cyclobentenone with lactones at a molar ratio of 1:1, and separating one of the optically active forms from the resulting optically active mixture of cyclobentenone ether forms. , which is then hydrolyzed.

However, the same publication states that 4-hydroxy-2-allyl-2-
Cyclobentenone and (IR,5S)-6,6-dimethyl-4-hydroxy-8-oxabicyclo[8,1,01
Obtained when reacting with hexane-2-one (
IR,5S)-6,6-dimethyl-3-oxa-4(R
) -[1(R)-4-oxo-8-allyl-2-cyclopentenyloxy]bicyclo[8,1,0]hexan-2-one (hereinafter referred to as I-al) and (IR, 5s)
-6,6-dimethyl-8-oxa-4(R) -[1
(S) Production of cyclobentenone ethers of -4-oxo-3-allyl-2-cyclopentynyloxy]bicyclo[8,1,01hexan-2-one (hereinafter referred to as [I-bl, !-)] There is no mention of ratios at all, and judging from the examples in which this mixture is separated by column chromatography, it seems that [! -al/
The [I-bl ratio is quite low, and the method for obtaining [I-al] is not necessarily satisfactory.

(In addition, when 4-hydroxy-2-propargyl-2-cyclobentenone is used as a raw material, they are called [ff-al and [m-bl], respectively, corresponding to the above example.) Therefore, in the above reaction, Obtaining one of the cyclobentenone ethers in an excess amount relative to its enantiomer is extremely important from the economic and purification standpoints.

For these reasons, the present inventors have improved the problems of the above-mentioned method, and have developed an optically active 4-HFO-+
As a result of investigation to produce 2-substituted-2-cyclopente):/', it was found that lactones and 4-hydroxy-2-substituted-2-cyclobentenone were used in a specific reaction molar ratio and in the presence of a specific catalyst. By performing the following reaction, it is possible to obtain a reaction mixture containing an excess amount of one of the optically active forms relative to its enantiomer, and as a result, isolation of the optically active form becomes very easy. The subsequent hydrolysis reaction also
This series of processes can be easily carried out using only water without the need for any organic solvent or the like, and the desired optically active 4-hydroxy-2-substituted-2-cyclobentenone can be obtained extremely advantageously. The present inventors have discovered that the present invention can be obtained, and have completed the present invention.

That is, the present invention provides 4- represented by general formula (11) (wherein R has the same meaning as above).
Hydroxy-2-! ! -2-cyclobentenone and (I
R,5s)-6,6-dimethyl-4-hydroxy-8-
Oxabicyclo[8,1,(N-hexane-2-one or (Is,5R)-6,6-dimethyl-4-hydroxy-8-oxabicyclo[8,1,0]hexane-2-
lactones of 1.5 to 2:1 in a molar ratio of 1.5 to 2:1 in the presence of para-toluenesulfonic acid or benzenesulfonic acid in an azeotropic solvent with azeotropic dehydration to form the general formula (
2) is a condensation product of 4-hydroxy-2-substituted-2-cyclobentenone and lactones, which is an optically active mixture of cyclobentenone ethers that produce an excess of one of the enantiomers. The optically active 4-hydroxy-2-substituted-2- represented by the general formula (1) is characterized in that the optically active 4-hydroxy-2-substituted-2- A method for producing cyclobentenone is provided.

The present invention will be explained in detail below.

In the reaction between 4-hydroxy-2-substituted-2-cyclobentenone and lactones, the reaction molar ratio between the two is very important;゜5 to 2 times the molar amount is used.

Only for such molar ratios, for example, [I-allCI
-b] ratio is specifically improved, that is, the excess of one optically active substance becomes high, and outside this molar ratio range, the excess decreases, which is not preferable.

Para-toluenesulfonic acid or benzenesulfonic acid is used as the catalyst, and their pyridine salts are not preferred, for example, in view of the produced [I-a]/[I-bl ratio.

The amount of the catalyst used is 0.01 to 005 times equivalent, preferably 0.01 to 0.2 times equivalent, relative to the lactone.

As the reaction solvent, a so-called azeotropic solvent that is azeotropic with water is used, and representative examples include benzene and toluene.

Since this reaction is a condensation reaction that produces water, it is necessary to proceed while the produced water is removed from the reaction system by azeotroping with the azeotropic solvent. At this time, the azeotropic solvent distilled off together with the water can be returned to the reaction system after separation from the water.

The reaction temperature is a temperature at which the azeotropic solvent can be azeotroped with water, and is usually 50 to 120°C, preferably 60 to 115°C.

The reaction time varies depending on various conditions and is not limited in any way, but is generally 2 to 7 hours.

Thus, for example, (IR, 5
5) Using -6,6-dimethyl-4-hydroxy-8-oxabicyclo[8,1,01 hexan-2-one,
When 4-hydroxy-2-allyl-2-cyclobentenone is used as the 4-hydroxy-2-tl-substituted-2-cyclobentenone, an excessive amount of [1-al-containing [I
-al and CI-b] is obtained, likewise using 4-hydroxy-2-propargyl-2-cyclobentenone, in this case containing an excess of [II-a] [u-
A mixture of a3 and [n-b] is obtained.

Also, as lactones (IS, 5K) -6゜6
-Simethyl-4-hydroxy-8-oxabicyclo[8
, 1,03hexan-2-one and 4-hydroxy-2-allyl-2-cyclobentenone as 4-hydroxy-2-[substituted-2-cyclobentenone, the excess amount (Is, 5K)-13,6-dimethyl-3-oxa-4(S)-[t(S)-4-oxo-3-allyl-2-cyclopentenyloxy]bicyclo[8,1,Olhexane- 2-one (hereinafter (1-dl)
[I-dl and (IS,5R)-6,6-
Cymethyl-8-oxa-4(S)-[1(R)-4
-oxo-8-allyl-2-cyclopentenyloxy]
Bicyclo[8°1.0]hexane-2-one (hereinafter [!
Correspondingly, if 4-hydroxy-2-propargyl-2-cyclobentenone is used, a mixture of [1 A mixture of -dl and (u-C1 is obtained.

[I-al or (x-a
) to [1-bl marj, t[m-b]sc or [I-dl or [I[-d] to [l-Cl or [1t-cl], 58-
This is higher than the excess in the mixture obtained by the method specifically disclosed in Publication No. 41886.

There are various methods for isolating the excess optically active cyclobentenone ether from such an optically active mixture of cyclobentenone ethers, but a method using column chromatography is advantageous.

In the case of column chromatography, silica gel, alumina, etc. can be used as a carrier, and the amount used is usually 4 to 70 times the weight of the cyclobentenone ether as a raw material.

The solvent used is one or a mixture of conventional solvents such as toluene, ethyl acetate, hexane, petroleum ether, isopropyl alcohol, and dichloromethane.

By such a separation means, the optically active cyclobentenone ether can be efficiently extracted with high optical purity.

The optically active cyclobentenone ether isolated in this way is then hydrolyzed, but this hydrolysis is carried out in an intermediate manner, considering the stability of the optically active 4-hydroxy-2-substituted-2-cyclobentenone. It is preferable to carry out the test under normal conditions.

Hydrolysis is carried out by heating in water or a mixed solvent of water and a water-soluble organic solvent (eg dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, etc.).

However, an organic solvent is not necessarily necessary, and considering post-treatment and purification after hydrolysis, it is preferable to use as little organic solvent as possible. Usually, the optically active cyclobentenone ether is mixed in 2 to 20 times its weight in water. This is done by heating.

The reaction temperature is usually 50-100°C, preferably 60-100°C.
The temperature is 0° C., and the reaction time is not particularly limited.

By this method, the optically active 4-hydroxy-2-substituted-2-cyclobentenone represented by the general formula (I) can be easily obtained in a good yield.

After completion of the reaction, lactones and optically active 4-hydroxy-2-substituted-2-cyclobentenone can be separated from the reaction mixture by, for example, cooling the reaction solution as it is, or cooling it after concentration to precipitate it. This is carried out by separating the lactones into P and then concentrating the F solution to obtain the desired optically active 4-hydroxy-2-@substituted-2-cyclopentenosyl compound. If necessary, such optical activity 4
-Hydroxy-2-substituted-2-cyclobentenone can also be purified by chromatography or distillation.

Thus, according to the method of the present invention, optically active 4-hydroxy-2-substituted-2-cyclobentenone can be obtained industrially easily and in good yield.

The present invention will be explained below with reference to Examples.

Example 1 4-Hydroxy-2-allyl-2-cyclobentenone 24°42f (0,177 mol), (IR
,5s)-6.

6-dimethyl-4-hydroxy-8-oxabisiglo [
8,1,0]hexan-2-one 16.76F(0,1
18 mol), 0.44 f of p-toluenesulfonic acid, and 150 m of benzene were charged, and the mixture was heated to reflux.

The reaction is allowed to proceed for 4 hours while the produced water is taken out of the reaction system. After the reaction is complete, 80% of water is added to disperse the organic layer. The organic layer is further washed with 60 gt of 8% sodium hydrogen aqueous solution and 70 gt of water. The organic layer was condensed under reduced pressure and (
IR,5S)-6,6-dimethyl-3-oxa-4(R
) -[1(R) -4-oxo-8-allyl-2-cyclopentenyloxynobicyclo CB, 1. OE hexan-2-one [I-a) and (l R,5S )-6,
6-cymethy71/-8-oxa-4(R)-41(S)
-4-oxo-8-allyl-2-cyclopentenyloxynobicyclo[8,1,Olhexan-2-one[I-
A mixture of 82°1f of bl was obtained.

[I-a]/[lb] = 1゜68 The above mixture was separated and purified by silica gel column chromatography INII dichloromethane:ethyl acetate = 100:1)im.
I-a,] 18.42 fft is obtained.

aJn -55,9° ((=:l, ethanol) Next, [1-a]8F was mixed with 1ml of water at 75"C.
Heat for an hour. After the reaction is completed, the reaction mixture is concentrated under reduced pressure to distill off about 4-4% of water, and then cooled to O''C and held for 8 hours. The precipitated crystals (lactone) are separated from each other, and the P solution is further concentrated. The concentrated residue is purified by chromatography to obtain 1.529 of 4(R)-hydroxy-2-allyl-2-cyclobentenone.

α)D+19.8° (C==l, methanol)n;'
1.5044 Example 2 In a device similar to that used in Example 1, 4-hydroxy-2
-Propargyl-2-cyclobentenone 21.76g (
0,16 mol), (IR25S)-6,6-dimethyl-4-hydroxy-8-oxabicyclo[8,1,03hexan-2-one 14.2 F (0,1 mol), benzenesulfonic acid 0, 8f and toluene 11005i are charged and azeotropically dehydrated at 80-85''C under reduced pressure.

The reaction time requires 4 hours.

After the reaction is complete, 6 (ld) of water is added and the organic layer is separated. The organic layer is further washed with 50 Ilt of 3% deuterated water and 60 m of water. The organic layer is concentrated under reduced pressure to obtain (IR, 5S
)-6,6-dimethyl-8-oxa-4(R)-(1(
R) -4-oxygen-8-propargyl-2-cyclopentenyloxy]bicyclo[8,1,0]hexan-2-one[I
[-a] and (tR,5S)-6,6-dimethyl-8-oxa-4(R)-[1(S)-4-oxo-3-propargyl-2-cyclopentenyloxy]bicyclo[8
°l, 0] mixture of hexan-2-one [II-bl 2
5.74f was obtained.

[M-a]/[II-b] = 1.6 The above mixture was separated and purified by silica gel column chromatography (solvent dichloromethane: ethyl acetate = 100:2) to obtain [1
-a315.22'f is obtained.

αJD -77,1' (c=1.ethanol) no
ol, 52 Q 5 Next, this [II-a 35 f with water 15-
Heat at 5-80°C for 8 hours. Thereafter, the product was post-treated and purified according to Example 1 to obtain 4(R)-hydroxy-2-propargyl-2-cyclobentenone 2°491.

α]D +IO, 8°(””t+chloroform)n2@i. 5187 Example 8 (IR,5s)-6,6-dimethyl-4-hydroxy-
(Is, 5R)-6,6-dimethyl-4-hydroxy-8-oxabicyclo[8,1,0]hexane-2-one instead of 3-oxabicyclo[3,1°O]hexane-2-one (IS, 5R)-6,6-dimethyl-8-
Oxa-4(S)-[1(S)-4-oxo-8-pargyl-2-cyclopentenyloxy]bicyclo[
8゜1,O]hexan-2-one [n-dl and (I S
, 5R)-6,6-dimethyl-8-oxa-4C3
)-[1(R)-4-oxo-8-propargyl-2-
A mixture of cyclopentenyloxy]bicyclo[8,1,Olhexan-2-one[I-cl] 31.8F was obtained.

This mixture was subjected to column chromatography for 1 ml.
1I! ll to obtain [1-d] l 5°16f.

a J o + 76.9° (c = 1. ethanol) nlD 1.6199 Next, add this [1[-d15N with water 15- to 75~8
Heat at 0°C for 8 hours. Thereafter, the product is post-treated and purified according to Example 1 to obtain 4(S)-hydroxy-2-propargyl-2-cyclobentenone 2.51f.

αJ:. -10,2° (c=1, chloroform) no' 1.5184

Claims (4)

[Claims] (1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents an allyl group or a propargyl group.) 4-hydroxy-2-substituted-2-cyclopentenone and (1R, 5S)-6,6-dimethyl-4-hydroxy-3-oxabicyclo[3,1,0]hexane-
2-one or (1S,5R)-6,6-dimethyl-
Lactones of 4-hydroxy-3-oxabicyclo[3,1,0]hexan-2-one were mixed at a molar ratio of 1.5 to 2:
Step 1 is reacted with azeotropic dehydration in an azeotropic solvent in the presence of paratoluenesulfonic acid or benzenesulfonic acid to form a condensate of 4-hydroxy-2-substituted-2-cyclopentenone and lactones. The method is characterized in that an optically active mixture of cyclopentenone ethers containing an excess amount of either enantiomer is obtained, the optically active mixture is separated to isolate an optically active cyclopentenone ether, and then hydrolyzed. A method for producing optically active 4-hydroxy-2-substituted-2-cyclopentenone represented by the general formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R has the same meaning as above.) (2) The method according to claim 1, wherein the amount of paratoluenesulfonic acid or benzenesulfonic acid used is 0.01 to 0.2 equivalents relative to the lactone. (3) The method according to claim 1, wherein the azeotropic dehydration temperature is 60 to 115°C. (4) The method according to claim 1, wherein the azeotropic solvent is toluene or benzene. (6) The method according to claim 1, wherein the separation is performed by column chromatography.